Process for the preparation of midodrine, pharmaceutically acceptable salts thereof and intermediates

Abstract

The present invention provides for a novel process for the preparation of Midodrine or a pharmaceutically acceptable salt thereof comprising: (a) a step of reacting 2-amino-1-(2′,5′-dimethoxyphenyl) ethanol of formula (I) with an N-protected glycine of formula (II) containing an amino protecting group in the presence of 1,1′-carbonyldiimidazole (CDI); and (b) removing the amino protecting group by deprotection formula (I), formula (II), wherein R 1 is a benzyl, triphenylmethyl, tert-butyloxycarbonyl, or a benzyloxycarbonyl group. This results in an unexpectedly efficient and cost-effective process. Additionally, the process is simple and safe as all the intermediates and reagents involved in the process pose no safety risks. Further reaction of Midodrine with a pharmaceutically acceptable acid affords a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutically acceptable salt obtained from the process according to the present invention is Midodrine Hydrochloride.

1 . A process for the preparation of Midodrine or a pharmaceutically acceptable salt thereof comprising: 
 (a) reacting 2-amino-1-(2′,5′-dimethoxyphenyl) ethanol of formula 1 with an N-protected glycine of formula 2 containing an amino protecting group in the presence of 1,1′-carbonyldiimidazole (CDI); and    (b) removing the amino protecting group by deprotection                        wherein R 1  is a benzyl, triphenylmethyl, tert-butyloxycarbonyl, or a benzyloxycarbonyl group.      
   
   
       2 . The process according to  claim 1  wherein Midodrine is further reacted with an acid to afford a pharmaceutically acceptable salt thereof.  
   
   
       3 . The process according to  claim 1  or  2  wherein the pharmaceutically acceptable salt is Midodrine Hydrochloride.  
   
   
       4 . The process according to  claim 1  or  2  wherein CDI is in an organic solvent and the organic solvent is selected from the group consisting of C 2 -C 4  nitrile solvents, C 2 -C 7  ester solvents, C 1 -C 4  amide solvents and mixtures thereof.  
   
   
       5 . The process according to  claim 3  wherein CDI is in an organic solvent and the organic solvent is selected from the group consisting of C 2 -C 4  nitrile solvents, C 2 -C 7  ester solvents, C 1 -C 4  amide solvents and mixtures thereof.  
   
   
       6 . The process according to  claim 4  wherein the organic solvent is selected from the group consisting of ethyl acetate, acetonitrile, dimethylformamide and mixtures thereof.  
   
   
       7 . The process according to  claim 5  wherein the organic solvent is selected from the group consisting of ethyl acetate, acetonitrile, dimethylformamide and mixtures thereof.  
   
   
       8 . The process according to any one of claims  1 ,  2 ,  5 ,  6  or  7  wherein the deprotection comprises: 
 (a) a reaction with HCl; or    (b) a hydrogenation reaction.    
   
   
       9 . The process according to  claim 3  wherein the deprotection comprises: 
 (a) a reaction with HCl; or    (b) a hydrogenation reaction.    
   
   
       10 . The process according to  claim 4  wherein the deprotection comprises: 
 (a) a reaction with HCl; or    (b) a hydrogenation reaction.    
   
   
       11 . The process according to  claim 8  further comprising addition of HCl after the hydrogenation reaction to yield Midodrine Hydrochloride.  
   
   
       12 . The process according to  claim 9  or  10  further comprising addition of HCl after the hydrogenation reaction to yield Midodrine Hydrochloride.  
   
   
       13 . The process according to  claim 8  wherein the hydrogenation reaction is either a hydrogenation under pressure or a catalytic transfer hydrogenation.  
   
   
       14 . The process according to  claim 9  or  10  wherein the hydrogenation reaction is either a hydrogenation under pressure or a catalytic transfer hydrogenation.  
   
   
       15 . The process according to  claim 13  wherein the catalytic transfer hydrogenation is carried out in the presence of at least one catalytic transfer agent selected from the group consisting of cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, hydrazine and mixtures thereof.  
   
   
       16 . The process according to  claim 14  wherein the catalytic transfer hydrogenation is carried out in the presence of at least one catalytic transfer agent selected from the group consisting of cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, hydrazine and mixtures thereof.  
   
   
       17 . The process according to  claim 8  wherein the hydrogenation reaction is carried out in the presence of Pd/C or Pd black as catalyst.  
   
   
       18 . The process according to any one of claims  9 ,  10 ,  11 ,  13 ,  15  or  16  wherein the hydrogenation reaction is carried out in the presence of Pd/C or Pd black as catalyst.  
   
   
       19 . The process according to  claim 12  wherein the hydrogenation reaction is carried out in the presence of Pd/C or Pd black as catalyst.  
   
   
       20 . The process according to  claim 14  wherein the hydrogenation reaction is carried out in the presence of Pd/C or Pd black as catalyst.  
   
   
       21 . The process according to  claim 8  wherein the hydrogenation reaction is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetic acid and a mixture of acetic acid/ethanol.  
   
   
       22 . The process according to any one of claims  9 ,  10 ,  11 ,  13 ,  15 ,  16 ,  17 ,  19  or  20  wherein the hydrogenation reaction is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetic acid and a mixture of acetic acid/ethanol.  
   
   
       23 . The process according to  claim 12  wherein the hydrogenation reaction is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetic acid and a mixture of acetic acid/ethanol.  
   
   
       24 . The process according to  claim 14  wherein the hydrogenation reaction is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetic acid and a mixture of acetic acid/ethanol.  
   
   
       25 . The process according to  claim 18  wherein the hydrogenation reaction is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetic acid and a mixture of acetic acid/ethanol.  
   
   
       26 . The process according to  claim 8  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       27 . The process according to any one of claims  9 ,  10 ,  11 ,  13 ,  15 ,  16 ,  17 ,  19 ,  20 ,  21 ,  23 ,  24  or  25  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       28 . The process according to  claim 12  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       29 . The process according to  claim 14  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       30 . The process according to  claim 18  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       31 . The process according to  claim 22  wherein the hydrogenation reaction is carried out under a hydrogen pressure of about 40 to about 100 psi.  
   
   
       32 . The process according to  claim 8  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       33 . The process according to any one of claims  9 ,  10 ,  11 ,  13 ,  15 ,  16 ,  17 ,  19 ,  20 ,  21 ,  23 ,  24 ,  25 ,  26 ,  28 ,  29 ,  30  or  31  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       34 . The process according to  claim 12  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       35 . The process according to  claim 14  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       36 . The process according to  claim 18  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       37 . The process according to  claim 22  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       38 . The process according to  claim 27  wherein the hydrogenation reaction is carried out at a temperature of about 40° C. to about 70° C.  
   
   
       39 . The process according to any one of claims  1 ,  2 ,  5 ,  6 ,  7 ,  9  or  10  wherein the deprotection is carried out using hydrochloric acid at a temperature ranging from about 20° C. to about 50° C.  
   
   
       40 . The process according to  claim 3  wherein the deprotection is carried out using hydrochloric acid at a temperature ranging from about 20° C. to about 50° C.  
   
   
       41 . The process according to  claim 4  wherein the deprotection is carried out using hydrochloric acid at a temperature ranging from about 20° C. to about 50° C.  
   
   
       42 . The process according to  claim 8  wherein the deprotection is carried out using hydrochloric acid at a temperature ranging from about 20° C. to about 50° C.  
   
   
       43 . The process according to any one of claims  1 ,  2 ,  5 ,  6 ,  7 ,  9 ,  10 ,  40 ,  41  or  42  wherein the deprotection is carried out using hydrochloric acid in isopropanol.  
   
   
       44 . The process according to  claim 3  wherein the deprotection is carried out using hydrochloric acid in isopropanol.  
   
   
       45 . The process according to  claim 4  wherein the deprotection is carried out using hydrochloric acid in isopropanol.  
   
   
       46 . The process according to  claim 8  wherein the deprotection is carried out using hydrochloric acid in isopropanol.  
   
   
       47 . The process according to  claim 39  wherein the deprotection is carried out using hydrochloric acid in isopropanol.  
   
   
       48 . A process for the preparation of N-protected Midodrine intermediates of formula 8 by reacting 2-amino-1-(2′,5′-dimethoxyphenyl)-ethanol of formula 1 with an N-protected glycine of formula 2 in the presence of 1,1′-carbonyldiimidazole (CDI)  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a benzyl, triphenylmethyl, tert-butyloxycarbonyl, or a benzyloxycarbonyl group.  
   
   
       49 . The process according to  claim 48  wherein CDI is in an organic solvent selected from a group consisting of C 2 -C 4  nitrile solvents, C 2 -C 7  ester solvents, C 1 -C 4  amide solvents and mixtures thereof.  
   
   
       50 . The process according to  claim 49  wherein the organic solvent is selected from the group consisting of ethyl acetate, acetonitrile, dimethylformamide and mixtures thereof.  
   
   
       51 . A process for the preparation of Midodrine Hydrochloride comprising: 
 (a) reacting 2-amino-1-(2′,5′-dimethoxyphenyl) ethanol of formula 1 with an N-protected glycine of formula 2 containing an amino protecting group in the presence of 1,1′-carbonyldiimidazole (CDI) and in an organic solvent selected from a group consisting of ethyl acetate, acetonitrile and dimethylformamide, or mixtures thereof; and    (b) removing the amino protecting group and formation of the Hydrochloride salt by addition of HCl                        wherein R 1  is a benzyl, triphenylmethyl, tert-butyloxycarbonyl, or a benzyloxycarbonyl group.